Phosphodiesterase 6 delta (PDE6D) was originally identified as a regulatory (non-catalytic) subunit of the enzyme PDE6. PDE6 is expressed exclusively in photoreceptor cells, and plays a critical role in retinal phototransduction. (Stryer, L. (1991) J. Biol. Chem. 266:10711-14; (Florio, S. K. et al. (1996) J. Biol. Chem. 271:24036-47. The PDE6 holoenzyme exists as both membrane-associated and soluble forms, and only the membrane-associated form is active in phototransduction, whereas, only the soluble form contains the PDE6D subunit. PDE6D regulates the subcellular localization and thus the activity of PDE6, and the release of PDE6 from membranes is mediated by PDE6D. PDE6D has been observed to reduce light-induced cGMP hydrolysis in rod outer segments (Cook et al., J. Biol. Chem 276(7):5248-5255 (2001)), presumably by removing the PDE6 holoenzyme from the membrane. PDE6D solubilizes PDE6 by binding specifically to prenylated peptide sequences near the C-termini of the PDE6A and PDE6B subunits. PDE6D is referred to in the scientific literature using several different designations, including PDE delta, PDEδ, PDE6 delta, PDEδ, PDE6D and PDED.
PDE6D interacts specifically with a host of important cell signaling proteins through their post-translational modification with isoprenoid intermediates, which are products of the cholesterol biosynthetic pathway. One such modification is called prenylation and involves the attachment of phospholipids to proteins after translation, particularly the large class of GTP-binding proteins. Prenyl groups are important for proper cellular localization and trafficking. The availability of isoprenoid intermediates for prenylation of GTP-binding proteins has been associated with various cardiovascular, inflammatory, cancerous and neurological diseases. A reduction in the amount of available prenyl groups has been associated with improved endothelial function, decreased oxidative stress, decreased inflammation and increased neuroprotective effects.
Due to the possible role of PDE6 in several diseases, there is a need to develop PDE6 modulators.